The present invention relates to analogues of etoposide for the treatment of patients having a tumour, more particularly a tumour that is metastatic and/or that reduces an organ function. The invention also relates to an in vitro method of selecting a respective patient for treatment with an analogue of etoposide.
Etoposide is a chemotherapeutic drug derived from podophyllotoxin and acts as an inhibitor of topoisomerase II. The enzyme topoisomerase II induces transient DNA double strand breaks to enable modifications of DNA tertiary structure. Etoposide acts as a topoisomerase II poison leading to a stabilization of the cleavable complex, resulting in multiple non-repairable double strand breaks.
There are two isoforms of topoisomerase II, alpha and beta. Expression of topoisomerase II alpha is regulated with the cell cycle, with a gradual increase starting in the G1 phase that peaks in G2/M, whereas in quiescent cells or terminally differentiated cells topoisomerase II is extremely underregulated. The action of etoposide is cell cycle dependent with maximal activity during the G2-S phase.
Etoposide is an important anti-tumour drug and is commonly used against a number of diverse tumours, for example paediatric cancers including lymphatic lymphomas, rhabdomyosarcomas and neuroblastomas. Etoposide is also used in the treatment of many common cancers in adults. It is the first line therapy in a series of tumours, e.g. small cell lung cancer, diffuse large cell lymphoma, testicular germ cell tumour (testicular cancer) and Hodgkin lymphoma. Etoposide is also active in e.g. Non-Hodgkin lymphoma, AIDS-related Kaposi's sarcoma, bladder cancer, Ewing sarcoma, brain tumours and ovarian germ cell tumours. However, there are factors limiting the applicability of etoposide, such as poor water solubility, metabolic inactivation, toxicity with side effects such as leucopenia and neutropenia and the resistance against etoposide developing in the treated patients.
In cancer therapy, the chances of successful treatment and the prognosis of a tumour patient are highly dependent on the type and the localisation of the tumour. Metastatic tumours are tumours that have spread from their respective organ of origin to a different part of the body. The survival rate and the chances of successful treatment often depend on whether or not a tumour is local or has metastasised.
Metastasis occurs when tumour cells break away from a primary tumour and spread to other parts of the body via the blood and/or the lymphatic system, are deposited within normal tissue and finally proliferate to form a metastasis. Metastasis requires invasive growth of a tumour, that is, growth into the surrounding structures. Invasive growth often leads to a breach of the barrier to the blood and/or lymph vessels.
Metastases are a hallmark of malignancy. They are common in advanced or late-stage cancer. In order to be able to metastasise, malignant cells must be able to break away from the primary tumour and to degrade the extracellular matrix that separates the tumour from the surrounding normal tissue. Metastasising tumours have acquired additional mutations or capabilities as compared to non-metastasising tumours. This includes the ability to overcome the body's metastasis-preventing mechanisms, which for example involve metastasis suppressor proteins. The metastatic potential of tumour cells depends on the ability to breach body barriers like the base membrane, to actively migrate to a blood and/or lymph vessel, to invade the vessel and to exit it, to withstand attacks by the immune system during the migration in the body, and to proliferate and form a new tumour. Metastatic potential is a characteristic of malignant cancer cells and depends on individual genetic features of the tumour.
Metastasis is involved in most deaths from cancer. The ability of a tumour to form metastases (e.g. in advanced or end-stage cancer), makes the chances of successful treatment of the tumour patient drop considerably. In contrast to treatment of a non-metastasising tumour, after a tumour has metastasised, treatment of the patient often fails. Accordingly, initial success in the treatment of a patient having a non-metastasising tumour with a particular drug—let alone the mere successful completion of pre-clinical studies with the drug—does not predict success in treatment with the drug of a tumour that has formed metastases (a tumour that is metastatic). Thus, even though there are a number of treatment options for primary tumours, there remains a need for medicaments able to act efficiently on the more aggressive metastatic tumours.
Often organ function is reduced due to the presence of a tumour in the organ. Usually, invasive tumour growth as defined above is responsible for the reduction in organ function, if the tumour growth interferes with the physiological function of the organ, e.g. by destroying the morphological and/or physiological integrity. Examples are advanced or late-stage tumours. There is a need to provide compounds showing a therapeutic effect also on such (more aggressive) tumours. Again, whether a compound can be successfully used to treat such a tumour cannot be predicted from success of the compound in pre-clinical studies or in the treatment of tumours that do not reduce an organ function.
An important issue in the chemotherapy of tumours, which occurs in the case of many chemotherapeutic agents (including etoposide) is that a large number of patients initially respond to treatment but after a while lose sensitivity to the agent. This phenomenon is called resistance.
It is often mediated by expression of the MDR-1 gene which confers to the cells a multidrug-resistant phenotype. Expression of MDR-1 is e.g. observed in the resistance to etoposide and other naturally derived topoisomerase II inhibitors like anthracyclines and mitoxantrone. Multidrug-resistant cell clones are able to survive and proliferate despite the presence of cytotoxic agents (chemotherapeutic agents, chemotherapeutic drugs). The MDR-1 (multidrug resistance-1) gene encodes a protein called P-glycoprotein (permeability glycoprotein), an ABC-transporter. Expression of MDR-1 is linked to a poor prognosis.
Resistance against chemotherapeutic agents may also be mediated by other mechanisms, like down-regulation of pro-apoptotic mechanisms or up-regulation of anti-apoptotic mechanisms, increased metabolisation of the agent or down-regulation of its target (which is topoisomerase II in the case of etoposide).
WO 03/048166 A1 discloses a class of podophyllotoxins used for example for the treatment of tumour patients and the synthesis of these podophyllotoxins. The treatment of tumours that are metastatic or that reduce an organ function is not disclosed.